The β-lactam type antibiotics, namely penicillins and cephalosporins are frequently used antibiotics. It is known that β-lactamase produced by microorganisms hydrolyze the β-lactam ring thereby deactivating antibiotic activity. In order to reduce the effect of β-lactamase, the antibiotics are administered in combination with β-lactamase inhibitor. These inhibitors function by binding to the beta-lactamase enzymes more efficiently than the actual beta-lactam antibiotic itself. This combination allows the antibiotic to “do its job” without being degraded by the beta-lactamase enzymes. Several antibiotic/β-lactamase inhibitor combinations exist in the market for example, Ampicillin/Sulbactam, Amoxicillin/Clavulanate and Ticarcillin/Clavulanate. These β-lactam/β-lactamase inhibitor combination antibiotic are being used for the treatment of infections in the community and in the hospital setting.
Among many β-lactamase inhibitors that are known in the literature, compound of following formula is disclosed in U.S. Pat. No. 4,562,073,
wherein R1 is hydrogen or trialkylsilyl; R2 is hydrogen, trialkylsilyl or COOR2′ wherein R2′ is hydrogen, C1-18 alkyl, C2-7 alkoxymethyl, C3-8 alkylcarbonyloxymethyl, C4-9 alkylcarbonyloxyethyl, (C5-7 cycloalkyl)carbonyloxymethyl, C9-14 benzylcarbonyloxyalkyl, C3-8 alkoxycarbonylmethyl, C4-9 alkoxycarbonylethyl, phthalidyl, crotonolacton-4-yl, gamma.-butyrolacton-4-yl, halogenated C1-6 alkyl substituted with 1 to 3 halogen atoms, C1-6 alkoxy- or nitro-substituted or unsubstituted benzyl, benzhydryl, tetrahydropyranyl, dimethylaminoethyl, dimethylchlorosilyl, trichlorosilyl, (5-substituted C1-6 alkyl or phenyl or unsubstituted-2-oxo-1,3-dioxoden-4-yl)methyl, C8-13 benzoyloxyalkyl or group for forming a pharmaceutically acceptable salt; and R3 has the same meaning as above R2′. This patent describes a β-lactam inhibitor wherein R1═R2═R3═H, which hereinafter referred as Tazo.
We have focused our research to identify novel β-lactamase inhibitors and succeeded with novel 2-substituted methyl penam derivatives of the formula (I). The novel 2-substituted methyl penam derivatives of the formula (I) are β-lactamase inhibitors used in combination with β-lactam antibiotics. The novel compounds herein in combination with suitable β-lactam antibiotic are effective against a number of human or animal pathogens and clinical isolates.